The peroxisome biogenesis disorders (PBD) occur in approximately 1/25,000 live births and result from the loss of multiple peroxisomal metabolic activities. However, unlike most other metabolic diseases, the genes defective in the PBD do not encode the enzymes involved in these metabolic functions. Rather the PBD are caused by defects in peroxins, proteins that are involved in assembling the peroxisome. Dr. Gould proposes to continue investigation into the mechanism of peroxisome biogenesis in both yeast and human cell systems, maximizing the advantages of each. This research has already led to the identification and preliminary characterization of several novel peroxins. Also, the performance of this work at a pre-eminent center for the study of the PBD, together with the synergy derived from analysis of the process in both yeast and human cell systems, has led to the identification of 4 new genes responsible for the PBD. It is anticipated the aims of this proposal will further elucidate mechanisms of peroxisome biogenesis and how they are disrupted in the PBD.